Unlike other tissues which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normal glutarnate concentrations are maintained within brain tissue by energy-consuming transport systems. Under low energy conditions which occur during conditions of hypoglycemia, hypoxia or ischemia, cells can release glutamate. Under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by either blockage of synaptic transmission or by the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman et al, al, Annals of Neurology, Vol. 19, No. 2 (1986)].
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia caused by stroke, cardiac arrest or perinatal asphyxia. Agents which selectively act as agonists and stimulate binding can enhance cognition and can be used to treat cognitive disorders.
Glycine, alanine and serine have been shown to enhance the electrophysiological response induced by NMDA in cortical neurons [see J. W. Johnson et al, Nature, 325, 529 (1987)]. This potentiation has been shown to be independent of the strychnine-sensitive glycine receptor [see D. Grahm et al, Biochemistry, 24, 990 (1985)]. A strychnine-insensitive, sodium independent [.sup.3 H]glycine recognition site has been identified [see H. Kishimoto et al, J. Neurochem., 37, 1010 (1981)] and a correlation has been established between the regional distribution of [.sup.3 H]glycine and NMDA-sensitive L-[3H]glutamate binding sites [L. Nguyen et al, Abs. Soc, Neurosci., 13, 759 (1987)].
Compounds which interact with the glycine receptor have been demonstrated to enhance the performance of learning tasks in rats, thereby suggesting that glycine agonists are useful as cognitive enhancers [J. B. Monahan et al, Pharmacol. Blochem. Behav., 34, 349 (1989); G. E. Handelmann et al, Pharmacol. Blochem. Behav., 34, 823 (1989)] as well as antipsychotic agents [S. I. Deutsch, Neuropharmacol., 12, 1 (1989)].
It has been shown that the glycine receptor site is functionally linked to both the NMDA receptor site, as well as the phencyclidine (PCP) receptor site [see, for example, P. C. Contreras, Molec. Neurobiol., 1, 191 (1987)]. Thus, compounds which manifest an agonist effect on-the NMDA/glycine/PCP receptor complex, i.e., compounds which positively modulate the receptor complex, can be used to treat cognitive disorders and/or for cognitive enhancement. Compounds which manifest an antagonist effect, both competitive and non-competitive, can be used as neuroprotective agents, anticonvulsants, muscle relaxants and anxiolytics.
Several classes of imidazopyridine compounds having various pharmaceutical uses are known. For example, EP#120,589, published 3 Oct. 1984, describes certain imidazo-(1,2-a)pyridinylheterocyclic compounds for use as cardiotonic and antiulcer agents. Schering EP#33,094 published 5 Aug. 1981, describes 3,8-disubstituted-imidazo-(1,2-a)pyridine compounds for use as antisecretory and cyto-protective agents. Syntheiabo U.S. Pat. No. 4,650,796, published 19 Feb. 1986, describes 2-phenyl-3-acylaminomethylimidazoDyridine compounds as anxiolytic, hypnotic and anticonvulsant agents. Synthelabo U.S. Pat. No. 4,501,745 describes imidazo-(1,2-a)pyridinealkanoic acid derivatives as anxiolytic, hypnotic and anticonvulsant agents. Schering U.S. Pat. No. 4,450,164 describes phosphonic acid derivatives of imidazo(1,2-a)-pyridine compounds for use as treatment of gastrointestinal diseases such as ulcers. Siphar U.S. Pat. No. 3,539,582 discloses imidazo-(1,2-a)-pyridine-2,3-dicarboxylic acid and the corresponding esters and amides thereof having analeptic properties. [See also Casagrande et al, Farmaco. Ed. Sci. 23(12), 1141 (1968) for treating respiratory infections.] Asssle WO8903-833-A discloses 5-hydroxy-imidazo-(1,2-a) pyridine-2-ethylcarboxylate-3-carboxylic acid useful for treating osteoporosis. Merck U.S. Pat. No. 4,408,047 discloses substituted imidazo-(1,2-a)-pyridine-2,3-dicarboxylic acids and carboxylates having .beta.-adrenergic blocking activity. Merrell Dow EP #0394905 published 31 Oct. 1990, discloses carboxyindoles as NMDA antagonists, one such carboxyindole being 3-(2-carboxy-6-chloro-indol-3-yl)propionic acid.